NM_000533.5(PLP1):c.140T>C (p.Ile47Thr) AND Hereditary spastic paraplegia 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 3, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000463096.7

Allele description [Variation Report for NM_000533.5(PLP1):c.140T>C (p.Ile47Thr)]

NM_000533.5(PLP1):c.140T>C (p.Ile47Thr)

Genes:

RAB9B:RAB9B, member RAS oncogene family [Gene - OMIM - HGNC]
PLP1:proteolipid protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.2

Genomic location:

Preferred name:

NM_000533.5(PLP1):c.140T>C (p.Ile47Thr)

HGVS:

NC_000023.11:g.103785717T>C
NG_008863.2:g.14207T>C
NG_016452.2:g.51566A>G
NM_000533.5:c.140T>CMANE SELECT
NM_001128834.3:c.140T>C
NM_001305004.1:c.5-30T>C
NM_199478.3:c.140T>C
NP_000524.3:p.Ile47Thr
NP_001122306.1:p.Ile47Thr
NP_955772.1:p.Ile47Thr
NC_000023.10:g.103040646T>C
NM_000533.4:c.140T>C

Protein change:

I47T

Links:

dbSNP: rs1060500909

NCBI 1000 Genomes Browser:

rs1060500909

Molecular consequence:

NM_001305004.1:c.5-30T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000533.5:c.140T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001128834.3:c.140T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_199478.3:c.140T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary spastic paraplegia 2 (SPG2)
Synonyms:: SPASTIC PARAPLEGIA 2, X-LINKED; Spastic paraplegia 2
Identifiers:: MONDO: MONDO:0010733; MedGen: C1839264; Orphanet: 99015; OMIM: 312920

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544292	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 3, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24519770, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544292

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 3, 2016)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The spectrum of PLP1 gene mutations in patients with the classical form of the Pelizaeus-Merzbacher disease.

Hoffman-Zacharska D, Mierzewska H, Szczepanik E, Poznański J, Mazurczak T, Jakubiuk-Tomaszuk A, Mądry J, Kierdaszuk A, Bal J.

Med Wieku Rozwoj. 2013 Oct-Dec;17(4):293-300.

PubMed [citation]

PMID:: 24519770

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544292.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, this variant is a rare missense that segregates with disease in a single family and is predicted to affect protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to segregate with Pelizaeus-Merzbacher disease (PMD) in a single family (PMID: 24519770). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 47 of the PLP1 protein (p.Ile47Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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